Alzheimer clue: busy brain connections may have downside.

Brain areas that are chronically activated produce increased amounts of amyloid beta, the waxy protein implicated in Alzheimer's disease, a study in mice shows.

The work comes on the heels of a report, released 5 months ago, showing that brain areas switched on during daydreaming in young, healthy adults are largely the same spots found to be damaged in Alzheimer's patients. Combined, the studies suggest that steady activity in certain parts of the brain can contribute to the disease.

In the new study, scientists used electrical stimulation and injections of chemicals to either stimulate or turn off neurons, the primary brain cells, in mice. When activated neurons fire messages across synapses to other neurons, the chemical building blocks for amyloid beta are released into the fluid that fills the spaces among neurons in the brain. That's where amyloid beta forms into plaques in Alzheimer's patients.

In the mice, chronic stimulation of specific parts of the brain correlated with increased release of the building block chemicals, whereas less-frequent stimulation led to decreased release of them. David M. Holtzman, a neurologist at Washington University in St. Louis, and his colleagues report these findings in the Dec. 22, 2005 Neuron.

"This study provides important new data [connecting] neuronal activity and control of extracellular amyloid-beta levels," says Roberto Malinow, a neuroscientist at Cold Spring Harbor (N.Y.) Laboratory.

The earlier study in people suggested specific brain areas that might benefit from some downtime.

In the Aug. 24, 2005 Journal of Neuroscience, neuroscientist Randy L. Buckner and his colleagues at Washington University compared magnetic resonance images of the brains of Alzheimer's patients with images of the brains of healthy young people. A striking correlation emerged between areas damaged in Alzheimer's patients and regions activated during daydreaming and idle thought in the younger people. In the young people, some of these regions were also used in memory retrieval, suggesting that a lifetime of increased activity in those regions predisposes a person to poor recall.

"The data we saw . didn't provide a plausible biological mechanism for how the brain could regulate amyloid-beta levels," says Buckner, a Howard Hughes Medical Institute investigator now at Harvard University. "This [new] paper shows a way in which brain activity might regulate amyloid beta production."

The research doesn't necessarily contradict evidence that mentally strenuous activities such as reading or solving puzzles can protect against the disease (SN: 3/10/01, p. 148). Some research hints that such tasks, while revving up certain areas of the brain, shut down others that are prone to amyloid-beta accumulation, says Holtzman.

Many puzzles remain. For example, Malinow says, the cerebellum is a busy area of the brain, yet it is seldom affected in Alzheimer's patients. "I don't know if neuronal activity can be the only determinant,' he says.

Holtzman agrees that Alzheimer's risk is probably influenced by other factors, including genetic and environmental pressures. But if scientists can establish that chronic activity in some areas of the brain contributes to Alzheimer's disease, it might open the way for drug treatments that lessen that stimulation, says Holtzman. "By regulating some [brain] areas, you might affect the disease."

Treatments for Alzheimer's are sorely lacking (SN: 5/8/04, p. 296). The disease afflicts roughly 24 million people worldwide. The total could soar to 81 million by 2040, researchers report in the Dec. 17, 2005 Lancet.